The principal aim of this project is the detailed characterization of the antiviral activity and mechanism of action of new anti-HIV leads discovered by LDDRD. Current studies are focused upon: a) prostratin, a non tumor-promoting phorbol ester derivative capable of complete suppression of HIV cytopathicity in vitro; b) the calanolides, a novel subclass of HIV-1 specific reverse transcriptase inhibitor; c) conocurvone, an unusual trimeric naphthoquinone derivative from the Western Australian smokebush plant; d) the michellamines, unique dimeric naphthylisoquinoline alkaloids which inhibit HIV-1 and HIV-2 reverse transcriptases, as well as cell-cell fusion and syncytium formation; e) and, unprecedented peptides and proteins with highly potent and selective anti-HIV activities.